This executive summary accompanies the publication of 8th edition of “Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines.” These guidelines provide an extensive critical review of the literature related to management of thromboembolic disorders.

Since publication of the seventh American College of Chest Physicians (ACCP) supplement on antithrombotic and thrombolytic therapy, the results of clinical trials have provided important new information on the management of thromboembolic disorders, and the science of developing recommendations has advanced. In the accompanying supplement, we provide the new and updated recommendations and review several important changes that we have made in our guideline development process.

We again made a conscious effort to increase the participation of female authors and contributors from outside North America, the latter reflecting the widespread use and dissemination of these guidelines internationally. The grading system for the recommendations was adopted in 2006 by the ACCP for all its guidelines, is similar to the increasingly widely used Grades of Recommendation, Assessment, Development, and Evaluation approach, and is described in detail in one of the introductory chapters. While most of the evidence on which recommendations are made remains low quality in fields of pediatric thrombosis, thrombosis in pregnancy, and thrombosis in valvular heart disease, rigorous studies in other fields have resulted in new and strong evidence-based recommendations for many indications.

The American College of Chest Physicians (ACCP) invited a panel of experts, researchers, information scientists, and guideline methodologists to develop the eighth edition of ACCP evidence-based guidelines on antithrombotic and thrombolytic therapy. The process began with guideline authors specifying the population, intervention and alternative, and outcomes for each clinical question and defined criteria for eligible articles, including methodologic criteria, for each recommendation. The McMaster University Evidence-Based Practice Center, in collaboration with the guideline authors and methodologists, developed strategies and executed systematic searches for evidence. The resulting guidelines are organized in chapters that present a clear link between the evidence and the resulting recommendations. The panel identified questions in which resource allocation issues were particularly important and obtained input from consultants with expertise in economic analysis for these issues. Authors paid careful attention to the quality of underlying evidence and the balance between risks and benefits, both reflected in grades of recommendations. For recommendations that are particularly sensitive to underlying values and preferences, the panel made explicit the values underlying the recommendations. Thus, the process of making recommendations for the ACCP guidelines included explicit definition of questions, transparent eligibility criteria for including studies, comprehensive searches and methodologic assessment of studies, and specification of values and preferences and resource implications underlying recommendations where particularly relevant. In combination with our previous practice of grading recommendations according to their strength and the methodologic quality of the supporting studies, these methods establish our guideline methodology as evidence based.

This chapter describes the system used by the American College of Chest Physicians to grade recommendations for antithrombotic and thrombolytic therapy as part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Clinicians need to know if a recommendation is strong or weak, and the methodologic quality of the evidence underlying that recommendation. We determine the strength of a recommendation by considering the balance between the desirable effects of an intervention and the undesirable effects (incremental harms, burdens, and for select recommendations, costs). If the desirable effects outweigh the undesirable effects, we recommend that clinicians offer an intervention to typical patients. The uncertainty associated with the balance between the desirable and undesirable effects will determine the strength of recommendations. If we are confident that benefits do or do not outweigh harms, burden, and costs, we make a strong recommendation in our formulation, Grade 1. If we are less certain of the magnitude of the benefits and risks, burden, and costs, and thus their relative impact, we make a weaker Grade 2 recommendation.

For grading methodologic quality, randomized controlled trials (RCTs) begin as high-quality evidence (designated by “A”), but quality can decrease to moderate (“B”), or low (“C”) as a result of poor design and conduct of RCTs, imprecision, inconsistency of results, indirectness, or a high likelihood for reporting bias. Observational studies begin as low quality of evidence (C) but can increase in quality on the basis of very large treatment effects.

Strong (Grade 1) recommendations can be applied uniformly to most patients. Weak (Grade 2) suggestions require more judicious application, particularly considering patient values and preferences and, when resource limitations play an important role, issues of cost.

Although clinical guidelines may have substantial implications for allocation of health-care resources, these issues typically are not considered in the guideline development process or are only considered informally. This is a particular challenge for guidelines intended to be applicable in a diversity of settings. Based on theoretical and practical issues, we develop and apply a basic strategy for incorporating resource considerations into clinical guidelines. Formal economic assessments, such as cost-effectiveness analyses, provide a powerful tool to account for the health and economic implications of clinical guidelines. An acceptable tradeoff of money for health can depend highly on local considerations, and it is feasible to incorporate resource considerations into clinical guidelines. Although use of a “bright line” criterion for what constitutes an acceptable tradeoff of money for health has some appeal, this approach can lead to guidelines that are sensible in some contexts but unrealistic in others. One way to address this tension is through “resource aware” guidelines in which the recommendations are primarily based on scientific evaluations of efficacy supplemented by a review of evidence about the health and economic tradeoffs associated with various options. This approach limits the possibility that the guideline committee can make a universal recommendation based on resource considerations, but we expect it will encourage more thoughtful discussion of economic issues; greater sensitivity to the diversity of investment in health resource internationally; and, perhaps, innovative ways of overcoming resource barriers to the use of the most effective therapies.

This chapter describes the pharmacology of approved parenteral anticoagulants, including the indirect anticoagulants, unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and danaparoid as well as the direct thrombin inhibitors hirudin, bivalirudin, and argatroban. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation of thrombin factor Xa and other clotting factors. Heparin also binds to cells and other plasma proteins, endowing it with unpredictable pharmacokinetic and pharmacodynamic properties, and can lead to nonhemorrhagic side effects, such as heparin-induced thrombocytopenia (HIT) and osteoporosis. LMWHs have greater inhibitory activity against factor Xa than thrombin and exhibit less binding to cells and proteins than heparin. Consequently, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties, have a longer half-life than heparin, and have a lower risk of nonhemorrhagic side effects. LMWHs can be administered once or twice daily by subcutaneous injection, without anticoagulant monitoring. Based on their greater convenience, LMWHs have replaced UFH for many clinical indications.

Fondaparinux, a synthetic pentasaccharide, catalyzes the inhibition of factor Xa, but not thrombin, in an antithrombin-dependent fashion. Fondaparinux binds only to antithrombin; therefore, HIT and osteoporosis are unlikely to occur. Fondaparinux has excellent bioavailability when administered subcutaneously, has a longer half-life than LMWHs, and is given once daily by subcutaneous injection in fixed doses, without anticoagulant monitoring. Three parenteral direct thrombin inhibitors and danaparoid are approved as alternatives to heparin in HIT patients.

This article concerning the pharmacokinetics and pharmacodynamics of vitamin K antagonists (VKAs) is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). It describes the antithrombotic effect of the VKAs, the monitoring of anticoagulation intensity, and the clinical applications of VKA therapy and provides specific management recommendations. Grade 1 recommendations are strong and indicate that the benefits do or do not outweigh the risks, burdens, and costs. Grade 2 recommendations suggest that the individual patient’s values may lead to different choices. (For a full understanding of the grading, see the “Grades of Recommendation” chapter by Guyatt et al, CHEST 2008; 133:123S–131S.)

Among the key recommendations in this article are the following: for dosing of VKAs, we recommend the initiation of oral anticoagulation therapy, with doses between 5 mg and 10 mg for the first 1 or 2 days for most individuals, with subsequent dosing based on the international normalized ratio (INR) response (Grade 1B); we suggest against pharmacogenetic-based dosing until randomized data indicate that it is beneficial (Grade 2C); and in elderly and other patient subgroups who are debilitated or malnourished, we recommend a starting dose of ≤ 5 mg (Grade 1C). The article also includes several specific recommendations for the management of patients with nontherapeutic INRs, with INRs above the therapeutic range, and with bleeding whether the INR is therapeutic or elevated. For the use of vitamin K to reverse a mildly elevated INR, we recommend oral rather than subcutaneous administration (Grade 1A). For patients with life-threatening bleeding or intracranial hemorrhage, we recommend the use of prothrombin complex concentrates or recombinant factor VIIa to immediately reverse the INR (Grade 1C). For most patients who have a lupus inhibitor, we recommend a therapeutic target INR of 2.5 (range, 2.0 to 3.0) [Grade 1A]. We recommend that physicians who manage oral anticoagulation therapy do so in a systematic and coordinated fashion, incorporating patient education, systematic INR testing, tracking, follow-up, and good patient communication of results and dose adjustments [Grade 1B]. In patients who are suitably selected and trained, patient self-testing or patient self-management of dosing are effective alternative treatment models that result in improved quality of anticoagulation management, with greater time in the therapeutic range and fewer adverse events. Patient self-monitoring or self-management, however, is a choice made by patients and physicians that depends on many factors. We suggest that such therapeutic management be implemented where suitable (Grade 2B).

This article about currently available antiplatelet drugs is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). It describes the mechanism of action, pharmacokinetics, and pharmacodynamics of aspirin, reversible cyclooxygenase inhibitors, thienopyridines, and integrin αIIbβ3 receptor antagonists. The relationships among dose, efficacy, and safety are thoroughly discussed, with a mechanistic overview of randomized clinical trials. The article does not provide specific management recommendations; however, it does highlight important practical aspects related to antiplatelet therapy, including the optimal dose of aspirin, the variable balance of benefits and hazards in different clinical settings, and the issue of interindividual variability in response to antiplatelet drugs.

This chapter focuses on new antithrombotic drugs that are in phase II or III clinical testing. Development of these new agents was prompted by limitations of existing antiplatelet, anticoagulant, or fibrinolytic drugs. Addressing these unmet needs, this chapter (1) outlines the rationale for development of new antithrombotic agents, (2) describes the new antiplatelet, anticoagulant, and fibrinolytic drugs, and (3) provides clinical perspectives on the opportunities and challenges faced by these novel agents.

This article about hemorrhagic complications of anticoagulant and thrombolytic treatment is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Bleeding is the major complication of anticoagulant and fibrinolytic therapy. The criteria for defining the severity of bleeding vary considerably between studies, accounting in part for the variation in the rates of bleeding reported. The major determinants of vitamin K antagonist (VKA)-induced bleeding are the intensity of the anticoagulant effect, underlying patient characteristics, and the length of therapy. There is good evidence that VKA therapy, targeted international normalized ratio (INR) of 2.5 (range, 2.0-3.0), is associated with a lower risk of bleeding than therapy targeted at an INR > 3.0.

The risk of bleeding associated with IV unfractionated heparin (UFH) in patients with acute venous thromboembolism is < 3% in recent trials. This bleeding risk may increase with increasing heparin dosages and age (> 70 years). Low-molecular-weight heparin (LMWH) is associated with less major bleeding compared with UFH in acute venous thromboembolism. Higher doses of UFH and LMWH are associated with important increases in major bleeding in ischemic stroke. In ST-segment elevation myocardial infarction, addition of LMWH, hirudin, or its derivatives to thrombolytic therapy is associated with a small increase in the risk of major bleeding, whereas treatment with fondaparinux or UFH is associated with a lower risk of bleeding.

Thrombolytic therapy increases the risk of major bleeding 1.5-fold to threefold in patients with acute venous thromboembolism, ischemic stroke, or ST-elevation myocardial infarction.

This article discusses the perioperative management of antithrombotic therapy and is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). The primary objectives of this article are the following: (1) to address the perioperative management of patients who are receiving vitamin K antagonists (VKAs) or antiplatelet drugs, such as aspirin and clopidogrel, and require an elective surgical or other invasive procedures; and (2) to address the perioperative use of bridging anticoagulation, typically with low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH). A secondary objective is to address the perioperative management of such patients who require urgent surgery. The recommendations in this article incorporate the grading system that is discussed in this supplement (Guyatt G et al, CHEST 2008; 133:123S–131S). Briefly, Grade 1 recommendations are considered strong and indicate that the benefits do (or do not) outweigh risks, burden, and costs, whereas Grade 2 recommendations are referred to as suggestions and imply that individual patient values may lead to different management choices.

The key recommendations in this article include the following: in patients with a mechanical heart valve or atrial fibrillation or venous thromboembolism (VTE) at high risk for thromboembolism, we recommend bridging anticoagulation with therapeutic-dose subcutaneous (SC) LMWH or IV UFH over no bridging during temporary interruption of VKA therapy (Grade 1C); in patients with a mechanical heart valve or atrial fibrillation or VTE at moderate risk for thromboembolism, we suggest bridging anticoagulation with therapeutic-dose SC LMWH, therapeutic-dose IV UFH, or low-dose SC LMWH over no bridging during temporary interruption of VKA therapy (Grade 2C); in patients with a mechanical heart valve or atrial fibrillation or VTE at low risk for thromboembolism, we suggest low-dose SC LMWH or no bridging over bridging with therapeutic-dose SC LMWH or IV UFH (Grade 2C).

In patients with a bare metal coronary stent who require surgery within 6 weeks of stent placement, we recommend continuing aspirin and clopidogrel in the perioperative period (Grade 1C); in patients with a drug-eluting coronary stent who require surgery within 12 months of stent placement, we recommend continuing aspirin and clopidogrel in the perioperative period (Grade 1C).

In patients who are undergoing minor dental procedures and are receiving VKAs, we recommend continuing VKAs around the time of the procedure and coadministering an oral prohemostatic agent (Grade 1B); in patients who are undergoing minor dermatologic procedures and are receiving VKAs, we recommend continuing VKAs around the time of the procedure (Grade 1C); in patients who are undergoing cataract removal and are receiving VKAs, we recommend continuing VKAs around the time of the procedure (Grade 1C).

This chapter about the recognition, treatment, and prevention of heparin-induced thrombocytopenia (HIT) is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patient values may lead to different choices. Among the key recommendations in this chapter are the following: For patients receiving heparin in whom the clinician considers the risk of HIT to be > 1.0%, we recommend platelet count monitoring over no platelet count monitoring (Grade 1C). For patients who are receiving heparin or have received heparin within the previous 2 weeks, we recommend investigating for a diagnosis of HIT if the platelet count falls by ≥ 50%, and/or a thrombotic event occurs, between days 5 and 14 (inclusive) following initiation of heparin, even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia has occurred (Grade 1C). For patients with strongly suspected (or confirmed) HIT, whether or not complicated by thrombosis, we recommend use of an alternative, nonheparin anticoagulant (danaparoid [Grade 1B], lepirudin [Grade 1C], argatroban [Grade 1C], fondaparinux [Grade 2C], or bivalirudin [Grade 2C]) over the further use of unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) therapy or initiation/continuation of vitamin K antagonists (VKAs) [Grade 1B]. The guidelines include specific recommendations for nonheparin anticoagulant dosing that differ from the package inserts. For patients with strongly suspected or confirmed HIT, we recommend against the use of vitamin K antagonist (VKA) [coumarin] therapy until after the platelet count has substantially recovered (usually, to at least 150 × 109/L) over starting VKA therapy at a lower platelet count (Grade 1B); that VKA therapy be started only with low maintenance doses (maximum, 5 mg of warfarin or 6 mg of phenprocoumon) over higher initial doses (Grade 1B); and that the nonheparin anticoagulant (eg, lepirudin, argatroban, danaparoid) be continued until the platelet count has reached a stable plateau, the international normalized ratio (INR) has reached the intended target range, and after a minimum overlap of at least 5 days between nonheparin anticoagulation and VKA therapy rather than a shorter overlap (Grade 1B). For patients receiving VKAs at the time of diagnosis of HIT, we recommend use of vitamin K (10 mg po or 5 to 10 mg IV) [Grade 1C].

This article discusses the prevention of venous thromboembolism (VTE) and is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do or do not outweigh risks, burden, and costs. Grade 2 suggestions imply that individual patient values may lead to different choices (for a full discussion of the grading, see the “Grades of Recommendation” chapter by Guyatt et al). Among the key recommendations in this chapter are the following: we recommend that every hospital develop a formal strategy that addresses the prevention of VTE (Grade 1A). We recommend against the use of aspirin alone as thromboprophylaxis for any patient group (Grade 1A), and we recommend that mechanical methods of thromboprophylaxis be used primarily for patients at high bleeding risk (Grade 1A) or possibly as an adjunct to anticoagulant thromboprophylaxis (Grade 2A).

For patients undergoing major general surgery, we recommend thromboprophylaxis with a low-molecular-weight heparin (LMWH), low-dose unfractionated heparin (LDUH), or fondaparinux (each Grade 1A). We recommend routine thromboprophylaxis for all patients undergoing major gynecologic surgery or major, open urologic procedures (Grade 1A for both groups), with LMWH, LDUH, fondaparinux, or intermittent pneumatic compression (IPC).

For patients undergoing elective hip or knee arthroplasty, we recommend one of the following three anticoagulant agents: LMWH, fondaparinux, or a vitamin K antagonist (VKA); international normalized ratio (INR) target, 2.5; range, 2.0 to 3.0 (each Grade 1A). For patients undergoing hip fracture surgery (HFS), we recommend the routine use of fondaparinux (Grade 1A), LMWH (Grade 1B), a VKA (target INR, 2.5; range, 2.0 to 3.0) [Grade 1B], or LDUH (Grade 1B). We recommend that patients undergoing hip or knee arthroplasty or HFS receive thromboprophylaxis for a minimum of 10 days (Grade 1A); for hip arthroplasty and HFS, we recommend continuing thromboprophylaxis > 10 days and up to 35 days (Grade 1A). We recommend that all major trauma and all spinal cord injury (SCI) patients receive thromboprophylaxis (Grade 1A). In patients admitted to hospital with an acute medical illness, we recommend thromboprophylaxis with LMWH, LDUH, or fondaparinux (each Grade 1A). We recommend that, on admission to the ICU, all patients be assessed for their risk of VTE, and that most receive thromboprophylaxis (Grade 1A).

This chapter about treatment for venous thromboembolic disease is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do or do not outweigh risks, burden, and costs. Grade 2 suggests that individual patient values may lead to different choices (for a full understanding of the grading, see “Grades of Recommendation” chapter). Among the key recommendations in this chapter are the following: for patients with objectively confirmed deep vein thrombosis (DVT) or pulmonary embolism (PE), we recommend anticoagulant therapy with subcutaneous (SC) low-molecular-weight heparin (LMWH), monitored IV, or SC unfractionated heparin (UFH), unmonitored weight-based SC UFH, or SC fondaparinux (all Grade 1A). For patients with a high clinical suspicion of DVT or PE, we recommend treatment with anticoagulants while awaiting the outcome of diagnostic tests (Grade 1C). For patients with confirmed PE, we recommend early evaluation of the risks to benefits of thrombolytic therapy (Grade 1C); for those with hemodynamic compromise, we recommend short-course thrombolytic therapy (Grade 1B); and for those with nonmassive PE, we recommend against the use of thrombolytic therapy (Grade 1B). In acute DVT or PE, we recommend initial treatment with LMWH, UFH or fondaparinux for at least 5 days rather than a shorter period (Grade 1C); and initiation of vitamin K antagonists (VKAs) together with LMWH, UFH, or fondaparinux on the first treatment day, and discontinuation of these heparin preparations when the international normalized ratio (INR) is ≥ 2.0 for at least 24 h (Grade 1A). For patients with DVT or PE secondary to a transient (reversible) risk factor, we recommend treatment with a VKA for 3 months over treatment for shorter periods (Grade 1A). For patients with unprovoked DVT or PE, we recommend treatment with a VKA for at least 3 months (Grade 1A), and that all patients are then evaluated for the risks to benefits of indefinite therapy (Grade 1C). We recommend indefinite anticoagulant therapy for patients with a first unprovoked proximal DVT or PE and a low risk of bleeding when this is consistent with the patient’s preference (Grade 1A), and for most patients with a second unprovoked DVT (Grade 1A). We recommend that the dose of VKA be adjusted to maintain a target INR of 2.5 (INR range, 2.0 to 3.0) for all treatment durations (Grade 1A). We recommend at least 3 months of treatment with LMWH for patients with VTE and cancer (Grade 1A), followed by treatment with LMWH or VKA as long as the cancer is active (Grade 1C). For prevention of postthrombotic syndrome (PTS) after proximal DVT, we recommend use of an elastic compression stocking (Grade 1A). For DVT of the upper extremity, we recommend similar treatment as for DVT of the leg (Grade 1C). Selected patients with lower-extremity (Grade 2B) and upper-extremity (Grade 2C). DVT may be considered for thrombus removal, generally using catheter-based thrombolytic techniques. For extensive superficial vein thrombosis, we recommend treatment with prophylactic or intermediate doses of LMWH or intermediate doses of UFH for 4 weeks (Grade 1B).

This chapter about antithrombotic therapy in atrial fibrillation (AF) is part of the American College of Chest Physicians Evidence-Based Guidelines Clinical Practice Guidelines (8th Edition). Grade 1 recommendations indicate that most patients would make the same choice and Grade 2 suggests that individual patient’s values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2008; 133[suppl]:123S–131S). Among the key recommendations in this chapter are the following (all vitamin K antagonist [VKA] recommendations have a target international normalized ratio [INR] of 2.5; range 2.0–3.0, unless otherwise noted). In patients with AF, including those with paroxysmal AF, who have had a prior ischemic stroke, transient ischemic attack (TIA), or systemic embolism, we recommend long-term anticoagulation with an oral VKA, such as warfarin, because of the high risk of future ischemic stroke faced by this set of patients (Grade 1A). In patients with AF, including those with paroxysmal AF, who have two or more of the risk factors for future ischemic stroke listed immediately below, we recommend long-term anticoagulation with an oral VKA (Grade 1A). Two or more of the following risk factors apply: age >75 years, history of hypertension, diabetes mellitus, moderately or severely impaired left ventricular systolic function and/or heart failure. In patients with AF, including those with paroxysmal AF, with only one of the risk factors listed immediately above, we recommend long-term antithrombotic therapy (Grade 1A), either as anticoagulation with an oral VKA, such as warfarin (Grade 1A), or as aspirin, at a dose of 75–325 mg/d (Grade 1B). In these patients at intermediate risk of ischemic stroke we suggest a VKA rather than aspirin (Grade 2A). In patients with AF, including those with paroxysmal AF, age ≤75 years and with none of the other risk factors listed above, we recommend long-term aspirin therapy at a dose of 75–325 mg/d (Grade 1B), because of their low risk of ischemic stroke. For patients with atrial flutter, we recommend that antithrombotic therapy decisions follow the same risk-based recommendations as for AF (Grade 1C). For patients with AF and mitral stenosis, we recommend long-term anticoagulation with an oral VKA (Grade 1B). For patients with AF and prosthetic heart valves we recommend long-term anticoagulation with an oral VKA at an intensity appropriate for the specific type of prosthesis (Grade 1B). See CHEST 2008; 133(suppl):593S–629S. For patients with AF of ≥48 h or of unknown duration for whom pharmacologic or electrical cardioversion is planned, we recommend anticoagulation with an oral VKA, such as warfarin, for 3 weeks before elective cardioversion and for at least 4 weeks after sinus rhythm has been maintained (Grade 1C). For patients with AF of ≥ 48 h or of unknown duration undergoing pharmacological or electrical cardioversion, we also recommend either immediate anticoagulation with unfractionated IV heparin, or low-molecular-weight heparin (LMWH), or at least 5 days of warfarin by the time of cardioversion (achieving an INR of 2.0–3.0) as well as a screening multiplane transesophageal echocardiography (TEE). If no thrombus is seen, cardioversion is successful, and sinus rhythm is maintained, we recommend anticoagulation for at least 4 weeks. If a thrombus is seen on TEE, then cardioversion should be postponed and anticoagulation should be continued indefinitely. We recommend obtaining a repeat TEE before attempting later cardioversion (Grade 1B addressing the equivalence of TEE-guided vs non–TEE-guided cardioversion). For patients with AF of known duration <48 h, we suggest cardioversion without prolonged anticoagulation (Grade 2C). However, in patients without contraindications to anticoagulation, we suggest beginning IV heparin or LMWH at presentation (Grade 2C).

This chapter about antithrombotic therapy for valvular heart disease is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patient values might lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2008; 133[suppl]:123S–131S). Among the key recommendations in this chapter are the following: for patients with rheumatic mitral valve disease complicated singly or in combination by the presence of atrial fibrillation (AF), previous systemic embolism, or left atrial thrombus, we recommend vitamin K antagonist (VKA) therapy (Grade 1A). For patients with rheumatic mitral valve disease and normal sinus rhythm, without left atrial enlargement, we do not suggest antithrombotic therapy unless a separate indication exists (Grade 2C). For patients with mitral valve prolapse (MVP), not complicated by AF, who have not had systemic embolism, unexplained transient ischemic attacks, or ischemic stroke, we recommend against antithrombotic therapy (Grade 1C). In patients with mitral annular calcification complicated by systemic embolism or ischemic stroke, we recommend antiplatelet agent (APA) therapy (Grade 1B). For patients with isolated calcific aortic valve disease, we suggest against antithrombotic therapy (Grade 2C). But, for those with aortic valve disease who have experienced ischemic stroke, we suggest APA therapy (Grade 2C). For patients with stroke associated with aortic atherosclerotic lesions, we recommend low-dose aspirin (ASA) therapy (Grade 1C). For patients with cryptogenic ischemic stroke and a patent foramen ovale (PFO), we recommend APA therapy (Grade 1A). For patients with mechanical heart valves, we recommend VKA therapy (Grade 1A). For patients with mechanical heart valves and history of vascular disease or who have additional risk factors for thromboembolism, we recommend the addition of low-dose aspirin ASA to VKA therapy (Grade 1B). We suggest ASA not be added to long-term VKA therapy in patients with mechanical heart valves who are at particularly high risk of bleeding (Grade 2C). For patients with bioprosthetic heart valves, we recommend ASA (Grade 1B). For patients with bioprosthetic heart valves and additional risk factors for thromboembolism, we recommend VKA therapy (Grade 1C). For patients with infective endocarditis, we recommend against antithrombotic therapy, unless a separate indication exists (Grade 1B).

This article about treatment and prevention of stroke is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients’ values may lead to different choices (for a full understanding of the grading, see the “Grades of Recommendations” chapter by Guyatt et al, CHEST 2008; 133:123S–131S). Among the key recommendations in this chapter are the following: For patients with acute ischemic stroke, we recommend administration of IV tissue plasminogen activator (tPA) if treatment is initiated within 3 h of clearly defined symptom onset (Grade 1A). For patients with acute ischemic stroke of > 3 h but < 4.5 h, we suggest clinicians do not use IV tPA (Grade 2A). For patients with acute stroke onset of > 4.5 h, we recommend against the use of IV tPA (Grade 1A). For patients with acute ischemic stroke who are not receiving thrombolysis, we recommend early aspirin therapy (Grade 1A). For acute ischemic stroke patients with restricted mobility, we recommend prophylactic low-dose subcutaneous heparin or low-molecular-weight heparins (Grade 1A). For long-term stroke prevention in patients with noncardioembolic stroke or transient ischemic attack (TIA) [ie, atherothrombotic, lacunar, or cryptogenic], we recommend treatment with an antiplatelet agent (Grade 1A), including aspirin (recommended dose, 50–100 mg/d), the combination of aspirin and extended-release dipyridamole (25 mg/200 mg bid), or clopidogrel (75 mg qd). In these patients, we recommend use of the combination of aspirin and extended-release dipyridamole (25/200 mg bid) over aspirin (Grade 1A) and suggest clopidogrel over aspirin (Grade 2B), and recommend avoiding long-term use of the combination of aspirin and clopidogrel (Grade 1B). For patients who are allergic to aspirin, we recommend clopidogrel (Grade 1A). In patients with atrial fibrillation and a recent stroke or TIA, we recommend long-term oral anticoagulation (target international normalized ratio, 2.5; range, 2.0 to 3.0) [Grade 1A]. In patients with venous sinus thrombosis, we recommend unfractionated heparin (Grade 1B) or low-molecular-weight heparin (Grade 1B) over no anticoagulant therapy during the acute phase.

This chapter about antithrombotic therapy for coronary artery disease is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicans Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggestions are weaker as there is uncertainty regarding the benefits, risks and costs such that individual patients’ values may lead to different choices (for a full understanding of the grading see the “Grades of Recommendation for Antithrombotic Agents” chapter by Guyatt et al, CHEST 2008; 133[suppl]:123S–131S). Among the key recommendations are the following: for all patients presenting with non–ST-segment elevation (NSTE) acute coronary syndrome (ACS), without a clear allergy to aspirin, we recommend immediate aspirin (162 to 325 mg po) and then daily oral aspirin (75 to 100 mg) [Grade 1A]. For NSTE ACS patients who are at at least moderate risk for an ischemic event and who will undergo an early invasive management strategy, we recommend “upstream” treatment either with clopidogrel (300 mg po bolus, followed by 75 mg/d) or a small-molecule IV glycoprotein (GP) IIb/IIIa inhibitor (eptifibatide or tirofiban) [Grade 1A]. For NSTE ACS patients who are at least moderate risk for an ischemic event and for whom an early conservative or a delayed invasive strategy of management is to be used, we recommend “upstream” treatment with clopidogrel (300 mg oral bolus, followed by 75 mg/d) [Grade 1A]. For NSTE ACS patients who undergo PCI, we recommend treatment with both clopidogrel and an IV GP IIb/IIIa inhibitor (Grade 1A). We recommend a loading dose of 600 mg of clopidogrel given at least 2 h prior to planned PCI followed by 75 mg/d (Grade 1B). For all patients presenting with NSTE ACS, we recommend anticoagulation with UFH or LMWH or bivalirudin or fondaparinux over no anticoagulation (Grade 1A). For NSTE ACS patients who will undergo an early invasive strategy of management, we recommend UFH (with a GP IIb/IIIa inhibitor) over either LMWH or fondaparinux (Grade 1B). For NSTE ACS patients in whom an early conservative or a delayed invasive strategy of management is to be used, we recommend fondaparinux over enoxaparin (Grade 1A) and LMWH over UFH (Grade 1B). We recommend continuing LMWH during PCI treatment of patients with NSTE ACS when it has been started as the “upstream” anticoagulant (Grade 1B). In low- to moderate-risk patients with NSTE ACS undergoing PCI, we recommend either bivalirudin with provisional (“bail-out”) GP IIb/IIIa inhibitors or UFH plus a GP IIb/IIIa inhibitor over alternative antithrombotic regimens (Grade 1B).

This chapter about fibrinolytic, antiplatelet, and antithrombin treatment for acute ST-segment elevation (STE) myocardial infarction (MI) is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patient values may lead to different choices (for a full understanding of the grading see the chapter by Guyatt et al, CHEST 2008; 133[suppl]:123S–131S). Among the key recommendations in this chapter are the following: for patients with ischemic symptoms characteristic of acute MI of ≤ 12 h in duration and persistent STE, we recommend that all undergo rapid evaluation for reperfusion (primary percutaneous coronary intervention [PCI] or fibrinolytic) therapy and have a reperfusion strategy implemented promptly after contact with the health-care system (Grade 1A). For patients with ischemic symptoms characteristic of acute MI of ≤ 12 h in duration and persistent STE, we recommend administration of streptokinase, anistreplase, alteplase, reteplase, or tenecteplase over no fibrinolytic therapy (all Grade 1A). For patients with symptom duration ≤ 6 h, we recommend the administration of alteplase or tenecteplase over streptokinase (both Grade 1A). We recommend aspirin over no aspirin therapy followed by indefinite therapy (Grade 1A); we also recommend clopidogrel in addition to aspirin for up to 28 days (Grade 1A). In addition to aspirin and other antiplatelet therapies, we recommend the use of antithrombin therapy (eg, unfractionated heparin (UFH), enoxaparin, or fondaparinux) over no antithrombin therapy (Grade 1A), including for those patients receiving fibrinolysis (and regardless of which lytic agent is administered), primary PCI, or patients not receiving reperfusion therapy.

The following chapter devoted to antithrombotic therapy for chronic coronary artery disease (CAD) is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do or do not outweigh risks, burden, and costs. Grade 2 suggests that individual patient values may lead to different choices (for a full understanding of the grading see the “Grades of Recommendation” chapter by Guyatt et al in this supplement, CHEST 2008; 133[suppl]:123S–131S). Among the key recommendations in this chapter are the following: for patients with non–ST-segment elevation (NSTE)-acute coronary syndrome (ACS) we recommend daily oral aspirin (75–100 mg) [Grade 1A]. For patients with an aspirin allergy, we recommend clopidogrel, 75 mg/d (Grade 1A). For patients who have received clopidogrel and are scheduled for coronary bypass surgery, we suggest discontinuing clopidogrel for 5 days prior to the scheduled surgery (Grade 2A). For patients after myocardial infarction, after ACS, and those with stable CAD and patients after percutaneous coronary intervention (PCI), we recommend daily aspirin (75–100 mg) as indefinite therapy (Grade 1A). We recommend clopidogrel in combination with aspirin for patients experiencing ST-segment elevation (STE) and NSTE-ACS (Grade 1A). For patients with contraindications to aspirin, we recommend clopidogrel as monotherapy (Grade 1A). For long-term treatment after PCI in patients who receive antithrombotic agents such as clopidogrel or warfarin, we recommend aspirin (75 to 100 mg/d) [Grade 1B]. For patients who undergo bare metal stent placement, we recommend the combination of aspirin and clopidogrel for at least 4 weeks (Grade 1A). We recommend that patients receiving drug-eluting stents (DES) receive aspirin (325 mg/d for 3 months followed by 75–100 mg/d) and clopidogrel 75 mg/d for a minimum of 12 months (Grade 2B). For primary prevention in patients with moderate risk for a coronary event, we recommend aspirin, 75–100 mg/d, over either no antithrombotic therapy or vitamin K antagonist (Grade 1A).

This chapter is devoted to antithrombotic therapy for peripheral artery occlusive disease as part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients’ values may lead to different choices (for a full understanding of the grading see the “Grades of Recommendation” chapter by Guyatt et al, CHEST 2008; 133:123S–131S). Among the key recommendations in this chapter are the following: We recommend lifelong antiplatelet therapy in comparison to no antiplatelet therapy in pulmonary artery disease (PAD) patients with clinically manifest coronary or cerebrovascular disease (Grade 1A), and also in those without clinically manifest coronary or cerebrovascular disease (Grade 1B). In patients with PAD and intermittent claudication, we recommend against the use of anticoagulants (Grade 1A). For patients with moderate to severe disabling intermittent claudication who do not respond to exercise therapy, and who are not candidates for surgical or catheter-based intervention, we recommend cilostazol (Grade 1A). We suggest that clinicians not use cilostazol in those with less-disabling claudication (Grade 2A). In patients with short-term (< 14 days) arterial thrombosis or embolism, we suggest intraarterial thrombolytic therapy (Grade 2B), provided they are at low risk of myonecrosis and ischemic nerve damage developing during the time to achieve revascularization. For patients undergoing major vascular reconstructive procedures, we recommend IV unfractionated heparin (UFH) prior to the application of vascular cross clamps (Grade 1A). For all patients undergoing infrainguinal arterial reconstruction, we recommend aspirin (75–100 mg, begun preoperatively) [Grade 1A]. For routine autogenous vein infrainguinal bypass, we recommend aspirin (75–100 mg, begun preoperatively) [Grade 1A]. For routine prosthetic infrainguinal bypass, we recommend aspirin (75–100 mg, begun preoperatively) [Grade 1A]. In patients undergoing carotid endarterectomy, we recommend that aspirin, 75–100 mg, be administered preoperatively and continued indefinitely (75–100 mg/d) [Grade 1A]. In nonoperative patients with asymptomatic carotid stenosis (primary or recurrent), we suggest that dual antiplatelet therapy with aspirin and clopidogrel be avoided (Grade 1B). For all patients undergoing lower-extremity balloon angioplasty (with or without stenting), we recommend long-term aspirin, 75–100 mg/d (Grade 1C).

This article discusses the management of venous thromboembolism (VTE) and thrombophilia, as well as the use of antithrombotic agents, during pregnancy and is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that benefits do, or do not, outweigh risks, burden, and costs. Grade 2 recommendations are weaker and imply that the magnitude of the benefits and risks, burden, and costs are less certain. Support for recommendations may come from high-quality, moderate-quality or low-quality studies; labeled, respectively, A, B, and C.

Among the key recommendations in this chapter are the following: for pregnant women, in general, we recommend that vitamin K antagonists should be substituted with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) [Grade 1A], except perhaps in women with mechanical heart valves. For pregnant patients, we suggest LMWH over UFH for the prevention and treatment of VTE (Grade 2C). For pregnant women with acute VTE, we recommend that subcutaneous LMWH or UFH should be continued throughout pregnancy (Grade 1B) and suggest that anticoagulants should be continued for at least 6 weeks postpartum (for a total minimum duration of therapy of 6 months) [Grade 2C].

For pregnant patients with a single prior episode of VTE associated with a transient risk factor that is no longer present and no thrombophilia, we recommend clinical surveillance antepartum and anticoagulant prophylaxis postpartum (Grade 1C). For other pregnant women with a history of a single prior episode of VTE who are not receiving long-term anticoagulant therapy, we recommend one of the following, rather than routine care or full-dose anticoagulation: antepartum prophylactic LMWH/UFH or intermediate-dose LMWH/UFH or clinical surveillance throughout pregnancy plus postpartum anticoagulants (Grade 1C). For such patients with a higher risk thrombophilia, in addition to postpartum prophylaxis, we suggest antepartum prophylactic or intermediate-dose LMWH or prophylactic or intermediate-dose UFH, rather than clinical surveillance (Grade 2C). We suggest that pregnant women with multiple episodes of VTE who are not receiving long-term anticoagulants receive antepartum prophylactic, intermediate-dose, or adjusted-dose LMWH or intermediate or adjusted-dose UFH, followed by postpartum anticoagulants (Grade 2C). For those pregnant women with prior VTE who are receiving long-term anticoagulants, we recommend LMWH or UFH throughout pregnancy (either adjusted-dose LMWH or UFH, 75% of adjusted-dose LMWH, or intermediate-dose LMWH) followed by resumption of long-term anticoagulants postpartum (Grade 1C).

We suggest both antepartum and postpartum prophylaxis for pregnant women with no prior history of VTE but antithrombin deficiency (Grade 2C). For all other pregnant women with thrombophilia but no prior VTE, we suggest antepartum clinical surveillance or prophylactic LMWH or UFH, plus postpartum anticoagulants, rather than routine care (Grade 2C). For women with recurrent early pregnancy loss or unexplained late pregnancy loss, we recommend screening for antiphospholipid antibodies (APLAs) [Grade 1A].

For women with these pregnancy complications who test positive for APLAs and have no history of venous or arterial thrombosis, we recommend antepartum administration of prophylactic or intermediate-dose UFH or prophylactic LMWH combined with aspirin (Grade 1B). We recommend that the decision about anticoagulant management during pregnancy for pregnant women with mechanical heart valves include an assessment of additional risk factors for thromboembolism including valve type, position, and history of thromboembolism (Grade 1C). While patient values and preferences are important for all decisions regarding antithrombotic therapy in pregnancy, this is particularly so for women with mechanical heart valves. For these women, we recommend either adjusted-dose bid LMWH throughout pregnancy (Grade 1C), adjusted-dose UFH throughout pregnancy (Grade 1C), or one of these two regimens until the thirteenth week with warfarin substitution until close to delivery before restarting LMWH or UFH) [Grade 1C]. However, if a pregnant woman with a mechanical heart valve is judged to be at very high risk of thromboembolism and there are concerns about the efficacy and safety of LMWH or UFH as dosed above, we suggest vitamin K antagonists throughout pregnancy with replacement by UFH or LMWH close to delivery, after a thorough discussion of the potential risks and benefits of this approach (Grade 2C).

This chapter about antithrombotic therapy in neonates and children is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs, and Grade 2 suggests that individual patient values may lead to different choices (for a full understanding of the grading, see Guyatt et al in this supplement, pages 123S–131S). In this chapter, many recommendations are based on extrapolation of adult data, and the reader is referred to the appropriate chapters relating to guidelines for adult populations. Within this chapter, the majority of recommendations are separate for neonates and children, reflecting the significant differences in epidemiology of thrombosis and safety and efficacy of therapy in these two populations. Among the key recommendations in this chapter are the following: In children with first episode of venous thromboembolism (VTE), we recommend anticoagulant therapy with either unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) [Grade 1B]. Dosing of IV UFH should prolong the activated partial thromboplastin time (aPTT) to a range that corresponds to an anti-factor Xa assay (anti-FXa) level of 0.35 to 0.7 U/mL, whereas LMWH should achieve an anti-FXa level of 0.5 to 1.0 U/mL 4 h after an injection for twice-daily dosing. In neonates with first VTE, we suggest either anticoagulation or supportive care with radiologic monitoring and subsequent anticoagulation if extension of the thrombosis occurs during supportive care (Grade 2C). We recommend against the use of routine systemic thromboprophylaxis for children with central venous lines (Grade 1B). For children with cerebral sinovenous thrombosis (CSVT) without significant intracranial hemorrhage (ICH), we recommend anticoagulation initially with UFH, or LMWH and subsequently with LMWH or vitamin K antagonists (VKAs) for a minimum of 3 months (Grade 1B). For children with non–sickle-cell disease-related acute arterial ischemic stroke (AIS), we recommend UFH or LMWH or aspirin (1 to 5 mg/kg/d) as initial therapy until dissection and embolic causes have been excluded (Grade 1B). For neonates with a first AIS, in the absence of a documented ongoing cardioembolic source, we recommend against anticoagulation or aspirin therapy (Grade 1B).

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